1. Field of the Invention
A new method of drug formulation delivers more boron to malignant tumors and facilitates boron neutron capture therapy (BNCT) of cancers such as glioblastoma and malignant melanoma. Data indicate that the formulation method may improve BPA-mediated BNCT of cancer by a factor of as much as between 10 and 100 million and also offers a selectivity factor (i.e., ratio of the sensitivity of cancerous tissue to the sensitivity of normal tissue) of between 10 and 100 million.
2. Background of The Invention.
Boron neutron capture therapy (BNCT) is being developed as a treatment for cancer, including brain cancer and malignant melanoma. P-boronophenylalanine (BPA) was initially proposed as a boron (B) delivery drug for BNCT of malignant melanoma because it was postulated that this B-containing amino acid, by mimicking a melanin precursor, would selectively accumulate in melanoma cells. BPA does seem to selectively accumulate in cancer cells, apparently as a result of uptake by an amino acid transport system. For successful BNCT, tumor B concentrations of at least 20 ppm are thought to be necessary, but higher tumor B levels are desirable. Calculations indicate that for a given neutron exposure, doubling of the tumor B concentration can increase tumor cell kill by a factor of about 10,000 or more. Thus, even modest increases in the amount of B in tumor cells can dramatically improve the effectiveness of BNCT as a cancer treatment.
If amino acid transport systems accumulate BPA, then high extracellular concentrations of BPA should increase the amount of BPA entering cancer cells. I.V. infusion of BPA is the simplest route for delivering BPA to the tumor cells but is not widely used because at physiological pH (7.4), BPA exhibits poor water solubility (&lt;4 ppm). One option for increasing BPA solubility is the use of organic complexes. Boric acid is known to complex with monosaccharides. Monosaccharides also increase BPA's aqueous solubility. However, BPA exists in different forms at different pH values and complexing of BPA with monosaccharides is a pH dependent process. I.V. administration of BPA-monosaccharide complexes created by pH manipulation increases the delivery of B to tumor tissue.